Insulin-like growth factor-1 receptor activation prevents hydrogen peroxide-induced oxidative stress, mitochondrial dysfunction and apoptosis

Abstract

Vascular disease is the leading cause of morbidity and mortality. Oxidative stress can cause endothelial cell apoptosis. Low insulin like growth factor-1 (IGF-1) has been linked to adverse risk profile and increased vascular disease incidence. Since IGF-1 acts as an important survival factor for multiple cell types, we undertook this study to investigate whether IGF-1 favorably affects oxidative-stress mediated apoptosis of vascular endothelial cells. Exposure to hydrogen peroxide induced apoptotic changes (e.g. DNA fragmentation, altered mitochondrial membrane potential and caspase-3 activity) in human umbilical vein endothelial cells (HUVECs) in a time dependent manner. Addition of IGF-1 blocked the oxidative-stress effect parallel to IGF-1 receptor (IGF-1R) expression, and silencing the IGF-1R with small interference RNA attenuated the IGF-1 influence. Our findings show that enhanced IGF-1 signaling inhibits oxidative-stress induced apoptosis in HUVECs by reducing mitochondrial dysfunction. Specifically the protective mechanism of IGF-1 involves preserving the mitochondrial membrane potential, maintaining the mitochondrial retention of cytochrome-c, and reducing caspase-3 activity. These results may have therapeutic implications in preventing/reducing vascular disease associated endothelial dysfunction.

Bone Marrow–Derived MicroRNA‐223 Works as an Endocrine Genetic Signal in Vascular Endothelial Cells and Participates in Vascular Injury From Kawasaki Disease

“…Computational analysis suggested that human IGF1R, a key antiapoptosis gene in ECs, has a miR‐223 binding site in its 3′ untranslated region that is conserved among mouse, rat, and human . IGF1R is thus a potential direct target gene of miR‐223.…”

“…Computational analysis suggested that human IGF1R, a key antiapoptosis gene in ECs, has a miR-223 binding site in its 3 0 untranslated region that is conserved among mouse, rat, and human. 12,17 IGF1R is thus a potential direct target gene of miR-223. To test whether miR-223 is able to bind directly to IGF1R and inhibit its expression, a construct in which a fragment of the 3 0 untranslated region of IGF1R mRNA containing the conserved miR-223 binding sequence was cloned into a firefly luciferase reporter construct and transfected into HEK 293 cells.…”

Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

“…It is significant that in vitro treatment of endothelial cells and cardiomyocytes with recombinant IGF-1 decreases mitochondrial H 2 O 2 production (29). Treatment of cultured endothelial cells with IGF-1 also preserves ⌬ m , maintaining the mitochondrial retention of cytochrome c and reducing caspase-3 activation upon exposure to H 2 O 2 (76). Furthermore, overexpression of IGF-1 protects mice against high-fat diet feeding-induced increases in ROS generation, thus preventing mitochondrial damage (227).…”

Essential roles of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in the liver [Review]

“…1). In fact, it has been reported that IGF-I improves mitochondrial function in vitro [53] and in vivo [54]. IGF-IR activation prevented oxidative stress, mitochondrial dysfunction, and apoptosis in human umbilical vein endothelial cells (HUVEC) [53].…”